期刊
HEPATOLOGY
卷 72, 期 2, 页码 609-625出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.31041
关键词
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资金
- National Research Foundation of Korea - Korean government (MIST) [2018R1A2A1A05077608]
- Korea Mouse Phenotyping Project [2014M3A9D5A01073556]
- Intelligent Synthetic Biology Center Global Frontier Project [2011-0031955]
- National Institutes of Health [R01AA027532]
- National Research Foundation of Korea [2018R1A2A1A05077608] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Background and Aims Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD. Approach and Results Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in gamma delta T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4(+) T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1 beta expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of gamma delta T cells in mice and humans. Conclusions EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1 beta expression in Kupffer cells triggers IL-17A production in gamma delta T cells at the early stage that may accelerate IL-17A expression in CD4(+) T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.
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